A multiphasic study of presumed serotonin (5HT) agonists and antagonists is proposed. Electrophysiological studies have suggested the existence of more than one type of 5HT receptor in the CNS. In this application, extensive behavioral and biochemical studies of central serotonin systems are designed to obtain additional evidence for multiple serotonin receptors in the CNS. Behavioral models of different subtypes of 5HT receptors are proposed and will be tested. The 5HT motor syndrome and the twitch frequency of suprahyoideal muscles are proposed as models for 5HT receptors on motor neurons in the medulla and spinal cord; the L-5-hydroxytryptophan-induced rise in corticosterone as a model of hypothalamic 5HT receptors; turning in unilateral 5,7-dihydroxytryptamine lesioned rats and discrimative stimulus effects of 5HT agonist and/or raphe stimulation as models of other forebrain 5HT receptors. Biochemical studies of the presumed 5HT agonists and antagonists are planned. These studies are designed to test the hypothesis of multiple 5HT receptors. In vitro radioligand binding studies using 3H-LSD and 3H-5HT as radioligands will be used to characterize 5HT receptors in forebrain areas (hippocampus, amygdaloid area, limbic forebrain and hypothalamus) and in medulla and spinal cord; we will then compare the presumed 5HT agonists and antagonists in these systems. In in vivo studies, the effects of these drugs on presynaptic events, such as the turnover rate of 5HT, will be examined in the various forebrain areas and in medulla and spinal cord, as an indirect measure of receptor activity. Ultimately, we hope to develop a classification of subtypes of 5HT receptors in different areas of the CNS as defined in terms of the relative potencies of agonists and antagonists in these model systems. Considering the possible role of 5HT in sleep, sexual behavior, aggression and the etiology of psychotic depression, the characterization of subtypes of 5HT receptors may have important implications for pharmacological intervention in mental diseases.